Process for the preparation of fluvastatin sodium crystal from XIV

ABSTRACT

Provided is a process for preparing a polymorphic form of fluvastatin sodium, particularly Form XIV.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/871,916, filed Jun. 18, 2004, which claims the benefit ofU.S. Provisional Application Ser. Nos. 60/479, 182, filed Jun. 18, 2003;60/483,099, filed Jun. 30, 2003; 60/485,748, filed Jul. 10, 2003;60/493,793, filed Aug. 11, 2003; 60/507,954, filed Oct. 3, 2003 and60/545,466, filed Feb. 19, 2004, all of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to the antihypercholesterolemia andantilipidemia agent fluvastatin and, more particularly, to the solidstate properties of its monosodium salt.

BACKGROUND OF THE INVENTION

Complications of cardiovascular disease, such as myocardial infarction,stroke, and peripheral vascular disease account for half of the deathsin the United States. A high level of low density lipoprotein (LDL) inthe bloodstream has been linked to the formation of coronary lesionswhich obstruct the flow of blood and can rupture and promote thrombosis.Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9thed. 1996). Reducing plasma LDL levels has been shown to reduce the riskof clinical events in patients with cardiovascular disease and inpatients who are free of cardiovascular disease but who havehypercholesterolemia. Scandinavian Simvastatin Survival Study Group,1994; Lipid Research Clinics Program, 1984a, 1984b.

Statin drugs are currently the most therapeutically effective drugsavailable for reducing the level of LDL in the blood stream of a patientat risk for cardiovascular disease. This class of drugs includes, interalia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin.The mechanism of action of statin drugs has been elucidated in somedetail. They disrupt the synthesis of cholesterol and other sterols inthe liver by competitively inhibiting the3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoAreductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA tomevalonate, which is the rate determining step in the biosynthesis ofcholesterol. Consequently, its inhibition leads to a reduction in therate of formation of cholesterol in the liver.

[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoicacid is a statin drug. It is known by the trivial name fluvastatin andhas the molecular formula (I):

depicted in free acid form.

Fluvastatin is commercially available under the trade name Lescol®.Fluvastatin is supplied as a monosodium salt in capsules containing theequivalent of 20 and 40 mg of fluvastatin and in extended-releasetablets containing the equivalent of 80 mg of fluvastatin. Fluvastatinand its sodium salt are described in U.S. Pat. No. 4,739,073. In Example6(a) of the '073 patent, a methyl ester precursor of (±) fluvastatin washydrolyzed with sodium hydroxide in methanol, which yielded, afterevaporation of the methanol, crude fluvastatin sodium. In Example 6(b),the fluvastatin methyl ester was hydrolyzed with sodium hydroxide inethanol. After evaporation of the ethanol, the residue was taken up inwater and lyophilized. The lyophilized product had a melting point rangeof 194□C-197□C. In Example 8, the sodium salt was prepared by ringopening of fluvastatin lactone with sodium hydroxide in ethanol asdescribed in Example 6(b). The product of Example 8 produced an infraredspectrum in a KBr pellet with bands at: 3413, 2978, 2936, 1572 and 1216cm⁻¹.

According to U.S. Pat. No. 6,124,340, lyophilization of fluvastatinsodium as was performed in Examples 6(b) and 8 of the '073 patent yieldssolid fluvastatin sodium as a mixture of a crystalline form, designatedas Form A, and amorphous material. The '340 patent sets forth thespectroscopic properties of another crystal form of fluvastatin sodiumwhich is said to have low hygroscopicity and photostability. This otherform is called Form B in the '340 patent. It is characterized by aninfrared spectrum with bands at 3343, 2995, 1587, 1536, 1386, 1337, 1042and 1014 cm⁻¹ and by the following powder X-ray diffraction peakpositions and intensities.

°2θ d (Å) I/I_(O)(%) 4.063 21.728 100 11.056 7.996 2.9 11.328 7.805 5.512.210 7.243 45.2 12.965 6.823 34.6 14.925 5.931 9.3 15.277 5.795 4.515.750 5.622 18.5 16.350 5.417 10.6 17.760 4.990 17.6 18.320 4.839 14.318.875 4.698 11.3 19.396 4.573 7.0 19.701 4.503 13.4 20.395 4.351 13.521.329 4.163 8.5 21.785 4.076 15.9 22.610 3.929 7.5 23.868 3.725 5.424.281 3.663 3.6 24.463 3.636 3.6 25.446 3.498 5.6 25.655 3.470 3.626.357 3.379 3.3 27.040 3.295 2.8 28.747 3.103 3.4 29.940 2.982 2.832.165 2.781 1.6 35.173 2.549 1.0 37.131 2.419 1.3

Fluvastatin sodium Form A is said to have the following powder X-raydiffraction peak positions and intensities.

°2θ d (Å) I/I_(O) (%) 3.965 22.265 100 7.936 11.131 0.9 10.554 8.375 1.710.645 8.304 1.5 11.931 7.412 44.5 12.215 7.240 14.5 14.496 6.106 1.114.812 5.976 0.8 15.916 5.564 0.3 17.769 4.988 3.2 18.640 4.756 5.319.856 4.468 5.8 20.518 4.325 2.9 20.908 4.245 1.2 21.389 4.151 1.321.722 4.088 1.1 22.675 3.918 0.8 24.089 3.691 1.0 24.533 3.626 0.526.519 3.358 0.2 27.973 3.187 0.9 28.861 3.091

U.S. Patent Application Publication No. 2003/0032666 reports theexistence of four crystal forms of fluvastatin monosodium called FormsC, D, E and F. The water content of the forms ranges between 3 and 32%.The new crystal forms of fluvastatin sodium were obtained by storing thesamples under atmospheres ranging between 20 and 90% relative humidity.

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form C possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Å) Intensity 23.8 (vs) 11.8 (w) 7.8 (vs) 7.6 (vw) 7.4 (vw) 6.4 (vw)6.1 (vw) 5.90 (w) 5.00 (vw) 4.88 (w) 4.73 (m) 4.56 (w) 4.40 (vw) 4.12(vw) 4.03 (vw) 3.96 (vw) 3.50 (vw) 3.36 (vw) 2.93 (vw) wherein (vs) =very strong intensity; (s) = strong intensity; (m) = medium intensity;(w) = weak intensity; and (vw) = very weak intensity.

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form D possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Å) Intensity 24.6 (vs) 12.5 (w) 8.3 (vs) 7.4 (vw) 6.2 (m) 4.97 (w)4.85 (vw) 4.52 (vw) 4.40 (vw) 4.14 (vw) 3.96 (vw) 3.41 (vw) 3.10 (vw)

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form E possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Å) Intensity 27.6 (m) 13.9 (vw) 9.2 (m) 8.5 (vw) 8.1 (vw) 7.4 (vw)6.9 (s) 6.1 (vw) 4.98 (m) 4.77 (m) 4.63 (m) 4.15 (w) 4.03 (w) 3.97 (vw)3.52 (vw) 3.33 (vw) 3.08 (vw) 2.99 (vw)

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form F possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Å) Intensity 29.6 (w) 14.8 (vw) 9.9 (w) 8.6 (vw) 8.3 (vw) 7.4 (s) 6.6(vw) 6.2 (vw) 5.93 (w) 5.03 (m) 4.94 (m) 4.35 (vw) 4.23 (w) 3.98 (vw)3.54 (vw) 2.98 (vw)

It also deserves mention that International Publication No. WO 02/36563discloses crystal forms of enantiomerically pure [3R,5S] and [3S,5R]fluvastatin sodium.

The present invention also relates to fluvastatin sodium and theproperties that it can exhibit in the condensed phase. The occurrence ofdifferent crystal forms (polymorphism) is a property of some moleculesand molecular complexes. A single molecule, like the fluvastatin informula (I) or a salt complex like fluvastatin sodium, may give rise toa variety of solids having distinct physical properties like meltingpoint, X-ray diffraction pattern, infrared absorption fingerprint andNMR spectrum. The crystalline form may give rise to thermal behaviordifferent from that of the amorphous material or another crystallineform. Thermal behavior is measured in the laboratory by such techniquesas capillary melting point, thermogravimetric analysis (“TGA”) anddifferential scanning calorimetry (“DSC”) and can be used to distinguishsome polymorphic forms from others. The differences in the physicalproperties of different crystalline forms result from the orientationand intermolecular interactions of adjacent molecules (complexes) in thebulk solid. Accordingly, polymorphs are distinct solids sharing the samemolecular formula yet having distinct advantageous and/ordisadvantageous physical properties compared to other forms in thepolymorph family. These properties can be influenced by controlling theconditions under which the salt is obtained in solid form.

Exemplary solid state physical properties include the flowability of themilled solid. Flowability affects the ease with which the material ishandled during processing into a pharmaceutical product. When particlesof the powdered compound do not flow past each other easily, aformulation specialist must take that fact into account in developing atablet or capsule formulation, which may necessitate the use of glidantssuch as colloidal silicon dioxide, talc, starch or tribasic calciumphosphate.

One of the most important physical properties of pharmaceuticalpolymorphs is their solubility in aqueous solution, particularly theirsolubility in the gastric juices of a patient. For example, whereabsorption through the gastrointestinal tract is slow, it is oftendesirable for a drug that is unstable to conditions in the patient'sstomach or intestine to dissolve slowly so that it does not accumulatein a deleterious environment. On the other hand, the method is notadvantageous where the effectiveness of a drug correlates with peakbloodstream levels of the drug, as in the case of statin drugs. With astatin drug, provided the drug is rapidly absorbed by the GI system, amore rapidly dissolving form is likely to exhibit increasedeffectiveness over a comparable amount of a more slowly dissolving form.

It is often the case that the most rapidly dissolving solid state of acompound is amorphous. Amorphous forms are often less stable thancrystalline forms because they do not have many of the stabilizingintermolecular interactions that are present in crystalline forms. Withan amorphous form, therefore, stabilizing intermolecular interactions donot have to be broken when the compound goes into solution, and so thedissolution rate is not retarded. Although they are more rapidlydissolving than crystalline forms, amorphous forms of a compound canhave disadvantages. A compound, when it is in an amorphous state, isfrequently more hygroscopic than a crystalline form of the same compound(although exceptions abound, such as when the crystal has wide channelsthat allow water to enter and leave the crystal in response to changesin moisture density outside the crystal). Water has been implicated indrug stability problems. For instance, the decomposition of aspirinwhich leads to the characteristic smell of vinegar when an old bottle ofaspirin is opened is a hydrolysis reaction catalyzed by water. It isthus prudent when selecting a solid state form of a compound that is tobe used as a drug, and possibly stored for a long time between packagingand use, to select a form that has low permeability to water. In thecase of fluvastatin monosodium, a crystalline form designated Form B hasalready been discovered that is purportedly less hygroscopic than thepartially crystalline/partially amorphous form of the salt that isobtained by following procedures in U.S. Pat. No. 4,739,073.

Although six distinct crystalline forms of racemic fluvastatin sodiumhave been reported to date, and at least one of them is purported to beless hygroscopic that the solid state form originally reported by thediscovers of the compound, the discovery of yet other crystalline formsof fluvastatin sodium is desirable. The discovery of new crystallineforms and solvates of a pharmaceutically useful compound provides a newopportunity to improve the performance characteristics of apharmaceutical product by enlarging the repertoire of materials that aformulation scientist has available for designing. For example, newcrystalline forms can be used to design a pharmaceutical dosage form ofa drug with low hygroscopicity, a targeted release profile, consistentdosing (enabled by good flow of the tableting composition into thetableting die), or other desired characteristic. New polymorphic formsand solvates of fluvastatin have now been discovered.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a powder X-ray diffractogram of fluvastatin sodium FormXIV.

FIG. 2 depicts a DSC thermogram of fluvastatin sodium Form XIV.

FIG. 3 depicts an IR spectrum of fluvastatin sodium Form XIV scannedfrom 4000 to 400 cm⁻¹, while FIG. 3 a expands the 4000-1500 cm-⁻¹ regionof the spectrum and FIG. 3 b expands the 1500−400 cm⁻¹ region of thespectrum.

FIG. 4 depicts a powder X-ray diffractogram of fluvastatin sodium FormXIV, having an additional peak at 12.4±0.2 degrees two-theta.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for preparing acrystalline form of fluvastatin sodium characterized by a PXRD patternwith peaks at 3.8, 11.1, 12.9, 17.8 and 21.7±0.2 degrees two-thetacomprising:

-   -   a) combining a C₁ to C₄ alkyl ester of fluvastatin with        acetonitrile at a ratio of about 1:4-6 (Kg/L) of the ester to        acetonitrile, and with water at a ratio of about 1:1.3-1:2        (Kg/L) of the ester to the water, to obtain a mixture;    -   b) combining sodium hydroxide with the mixture to hydrolyze the        ester, thereby obtaining a solution, wherein if aqueous sodium        hydroxide is used, the water ratio does not exceed that provided        in step (a);    -   c) combining additional acetonitrile with the solution to        precipitate crystalline fluvastatin sodium; and    -   d) recovering crystalline fluvastatin sodium.        Preferably, the alkyl ester is combined with acetonitrile at a        ratio of about 1 :5-6(Kg/L). Preferably, the addition of the        acetonitrile in step (c) results in a ratio of about 1:15 to        about 1:25 (Kg/L), more preferably about 1:19.5-1:20.5 (Kg/L).        Preferably, the ratio of the ester to water is about 1:1.3-1:1.8        (Kg/L). Preferably, the solution is maintained after addition of        acetonitrile for about 2 to about 24 hours, more preferably for        about 5 hours. Preferably, prior to combining with acetonitrile,        the mixture is heated to a temperature of about 30° C. to about        40° C. to facilitate dissolution. More preferably, the mixture        is heated to a temperature of about 35° C. Preferably, after        heating, the solution is cooled to room temperature. Preferably,        the ester is t-butyl. When a butyl ester is not used, preferably        the ratio is calculated based on the weight of butyl ester.

In another aspect, the present invention provides a process forpreparing a crystalline form of fluvastatin sodium characterized by aPXRD pattern with peaks at 3.8, 11.1, 12.9, 17.8 and 21.7±0.2 degreestwo-theta comprising:

-   -   a) preparing a solution of fluvastatin sodium in acetonitrile at        a ratio of about 1:4-6 (Kg/L) of fluvastatin to acetonitrile,        and in water at a ratio of about 1:1.3-1:2 (Kg/L) of fluvastatin        to water, wherein the ratio is based on the molar weight of        butyl ester of fluvastatin;    -   b) combining the solution with an additional amount of        acetonitrile to precipitate the crystalline fluvastatin sodium;        and    -   c) recovering the crystalline fluvastatin sodium.        Preferably the fluvastatin to acetonitrile ratio is about 1:5-6        (Kg/L). Preferably addition of acetonitrile in step (b) results        in a ratio of about 1:15-1:25 (Kg/L), more preferably about        1:19.5 to 1:20.5 (Kg/L). Preferably the ratio of fluvastatin to        water is about 1:1.3-1:1.8 (Kg/L).

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a fluvastatin sodium formhaving a PXRD pattern (Form XIV) 3.8, 11.1, 12.9, 17.8 and 21.7±0.2degrees two-theta and a pharmaceutically acceptable excipient. Alsoprovided are pharmaceutical dosage forms from such compositions such astablets. Also provided are methods of treating a patient suffering fromhypercholesterolemia or hyperlipidemia comprising the step ofadministering to the patient an effective amount of this pharmaceuticalcomposition.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used in this disclosure, the term “elevated temperature” means atemperature above ambient temperature or above about 25° C. Preferredelevated temperatures are 50° C. and above and especially preferredelevated temperatures, when used in reference to contacting withparticular liquids, are the boiling points of such liquids.

The term “lower alkyl” means a C₁ to C₄ alkyl group.

The terms “suspend” or “slurry” refer to a heterogeneous mixture wherecomplete dissolution does not occur.

The present invention provides for a crystal form of[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoicacid monosodium (fluvastatin sodium). The crystalline form offluvastatin sodium has been designated Forms XIV. In so doing we haveopted to use Roman numerals as labels for the crystals instead of theRoman alphabetical labels used by others working in the field to labelother crystalline forms of fluvastatin sodium.

Whether the two enantiomers of [R*,S*-(E)]-(±) fluvastatin sodiumco-crystallize in a single unit cell or whether they crystallize inseparate unit cells that are mirror images of each other has yet to bedetermined for all of the new crystals forms. Accordingly, the crystalform of this invention is considered to include crystals that exhibitsubstantially the same PXRD patterns as those depicted in the figureswhether they are prepared starting from pure or enriched [R*,S*-(E)]-(+)and [R*,S*-(E)]-(−) fluvastatin sodium or racemic fluvastatin sodium.

By the crystallization processes of this invention fluvastatin sodiumForm XIV is obtained substantially free from other crystal forms, whichmeans less than 5% of any other crystal form as measured by X-ray powderdiffraction. The XRD pattern of Form B is significantly different fromthe XRD pattern of the novel crystal forms. Several XRD peaks of Form Bare not overlapping with the XRD peaks of the novel forms. Detection ofForm B is possible at 12.2, 16.4 and 22.6±0.2 degrees two theta.

Fluvastatin Form XIV is a hydrated form of fluvastatin sodium. The levelof water in fluvastatin sodium is measured by Karl Fisher using methodsknown in the art. Some of the new crystal forms of fluvastatin sodiumcontain residual solvent in addition to water, which is seen by the factthat the TGA weight loss value is significantly larger than the KarlFisher value. Some of the solvated crystal forms contain only smallquantities of residual solvent. Fluvastatin sodium Form XIV can be foundin the following hydrated states: monohydrate sesquihydrate, dihydrate(water content about 7-8%); trihydrate (water content about 11-13%);tetrahydrate (water content about 14-16%); hemipentahydrate,pentahydrate (water content 17-18%); Form XIV can be obtained with lessthan about 6% water, even as low as about 3% water by weight.

Fluvastatin is a known compound that can be purchased from commercialsources or synthesized by known processes such as the process disclosedin U.S. Pat. No. 4,739,073, which is incorporated herein by reference inits entirety. In particular, U.S. Pat. No. 4,739,073 is incorporatedherein for its disclosure of how to prepare fluvastatin and fluvastatinsodium. In the processes of this invention that use fluvastatin sodiumas a starting material, fluvastatin sodium Form B is the preferredstarting material unless otherwise indicated.

Fluvastatin sodium Form XIV produces a PXRD diffractogram withcharacteristic peaks at 3.8, 11.1, 12.9, 17.8 and 21.7±0.2 degreestwo-theta and other peaks at 9.2, 14.8, 15.7, 18.3, 20.3, 25.5 and26.9±0.2 degrees two-theta (FIG. 1). Some crystals have all the peaksassociated with Form XIV′ and exhibit many of characteristics of FormXIV, but have an additional peak at 12.4±0.2 degrees two-theta (FIG. 4).Fluvastatin sodium Form XIV produced the DSC thermogram shown in FIG. 2,in which two main endothermic peaks can be seen below 90° C. and atabout 110° C. The water content of the sample is about 7.1 wt. %. Theloss on drying by TGA is 7.5 wt. %. Fluvastatin sodium Form XIV wasstable after exposure to relative humidities between 0-100% RH for 8days and equilibrated at water contents of about 3-17%. Fluvastatin FormXIV is in monohydrate, sesquihydrate, dihydrate, hemipentahydrate,trihydrate, tetrahydrate, and pentahydrate forms. The IR spectrum offluvastatin sodium Form XIV is shown in FIGS. 3, 3 a and 3 b.

Form XIV has the appearance of a white to pale yellow powder. Stabilitystudies have shown that its appearance does not change after storage at40° C. for three months.

The present invention further provides a fluvastatin sodium Form XIV, ofwhich no more than about 5% transforms into Form B upon storage at atemperature of 25, 40 and 55° C., for at least 3 months (see table 1).

TABLE 1 Stability study of Form XIV Polymorph content by X-Ray PowderDiffraction analysis Results Time interval t = 0 25° C., 60% RH 40° C.,75% RH 55° C. XIV 1M XIV XIV XIV 2M XIV XIV XIV 3M XIV XIV XIV

Fluvastatin sodium Form XIV can be prepared by suspending fluvastatinsodium in a mixture of toluene and a C₅ to C₇ straight or branchedsaturated hydrocarbon such as hexanes to obtain a slurry, i.e., aheterogeneous mixture, for a period of time necessary to effect theconversion and then separating Form XIV from the mixture. Form XIV alsocan be prepared by storing Form VII under 100% RH for 11 days.

Fluvastatin sodium Form XIV also can be prepared directly from astraight or branched lower alkyl ester of fluvastatin. The startingmaterial is dissolved in a solution containing about 1 molar equivalentof sodium hydroxide in a solvent system selected from the groupconsisting of ethanol, mixtures of water and ethanol, propan-2-ol andmixtures of water and propan-2-ol, mixtures of THF and water andmixtures of propan-1-ol and water. Preferred mixtures contain about 8-9%water and 91-92% organic solvent, except for THF:water mixtures forwhich the mixture preferably contains about 5% water. The startingmaterial preferably is dissolved at elevated temperature, e.g. thereflux temperature of the solvent system. At elevated temperature, ananti-solvent selected from the group consisting of acetonitrile,hexanes, dichloromethane and MTBE is added at elevated temperature tothe solution to induce precipitation of Form XIV. Alternatively, theanti-solvent may be omitted and precipitation induced by cooling fromsome solvent systems, such as propan-2-ol:water mixtures. After allowingthe resulting mixture to cool, Form XIV can be separated from thesolvent system and anti-solvent by conventional techniques such asfiltering, decanting, centrifuging and the like, preferably filteringunder an inert atmosphere like nitrogen. The separated Form XIV may bedried. A suitable drying condition is 50° C. under vacuum.

According to an alternative process, Form XIV is prepared from astraight or branched lower alkyl ester of fluvastatin by hydrolyzing thestarting material in a solution containing about 1 molar equivalent ofsodium hydroxide in a solvent system containing water and an organicsolvent selected from the group consisting of methanol, ethanol and THF.After hydrolysis, the organic solvent is evaporated and, optionally,more water is added, the aqueous solution may be extracted with a waterimmiscible solvent such as ethyl acetate and Methyl t-Butyl Ether(MTBE). Then the water is evaporated and the residue is taken up inacetonitrile and allowed to recrystallize from the acetonitrile to yieldForm LXXXVII. If the amount water remaining after evaporation step istoo low, then Form B is obtained. Preferably after evaporation amount ofwater remaining is at least about 1 mL per gram of fluvastatin sodium.Form LXXXVII can be separated from the acetonitrile by conventionaltechniques such as filtering, decanting, centrifuiging and the like,preferably filtering under an inert atmosphere like nitrogen. Theseparated Form LXXVII may than be dried to obtain Form XIV. A suitabledrying condition is about 30° C. to about 60° C., such as about 40° C.or about 50° C., more preferably under vacuum. A preferred vacuumpressure is below about 100 mmHg, more preferably below about 50 mmHg.

Form XIV may also be prepared by adding portion wise MTBE, hexane,acetonitrile or dichloromethane, to a solution of fluvastatin sodium inethanol, propan-2-ol or tetrahydrofuran as a solvent, wherein thesolution is heated before, during or after of the addition, andrecovering the crystalline form. An example of portion wise addition isdropwise. In one embodiment, the anti-solvents are added dropwise,followed by heating, followed by cooling and stirring to recover thecrystalline form. The solvent may contain water, preferably less thanabout 10% by volume. In another embodiment, Form XIV is prepared bycombining a solution of fluvastatin sodium in water with iso-propylalcohol, ethyl acetate, acetonitrile or acetone. After addition, thereaction mixture may be stirred and the crystals recovered byconventional manner.

Form XIV can be prepared in high purity by the foregoing processes. Inaddition to being polymorphically pure, crystallization of fluvastatinsodium into Form XIV is especially effective at removing impurities. Forinstance, HPLC of samples of Form XIV shows that it typically containsless than 0.5% of hydroxy epimers of fluvastatin and less than 1% totalimpurities. HPLC was performed according to the method of PharmacopeialPreviews, 1999, 24, 8420.

Form XIV also can be prepared directly from a straight or branched loweralkyl ester of fluvastatin, such as a C₁ to C₄ ester. Examples of estersinclude methyl, ethyl, I-propyl and t-butyl. The ester is combined withwater and acetonitrile, followed by the addition of sodium hydroxide.The preferred ratio of the ester and water is about 1:1.3-1:2 (Kg/L),most preferably, the ratio is about 1:1.3-1:1.8 (Kg/L). The preferredratio of the ester and acetonitrile is preferably about 1:4-6 (Kg/L),more preferably about 1:5-6 (Kg/L). The weight is calculated based onthe ester, preferably a butyl ester. After addition of sodium hydroxide,the ester is hydrolyzed and a solution eventually forms.

The sodium hydroxide used may be either aqueous or solid. When anaqueous sodium hydroxide is used, the water present in such aqueoussolution is taken into account in the ratio.

Additional acetonitrile is then combined with the solution toprecipitate fluvastatin sodium. The final ratio of fluvastatin toacetonitrile is preferably 1:15-1:25 (Kg/L), more preferably about1:19.5 to 1:20.5 (Kg/L).

In the specific example provided, precipitation occurred spontaneouslyafter addition of acetonitrile, but the solution was maintained toincrease yield. The solution is preferably maintained for about 2 toabout 24 hours, more preferably for about 5 hours. The process of thepresent invention encompasses non-spontaneous precipitation afteraddition of acetonitrile to the solution. Form XIV may be recovered fromthe reaction mixture by conventional techniques such as filtering,decanting, centrifuging and the like, preferably filtering under vacuum.The recovered Form XIV may be washed, preferably with acetonitrile anddried. A suitable drying condition is about 40° C. under vacuum.

In addition to starting with the ester, the process may be carried outfrom a solution of fluvastatin sodium in the mixture of water andacetonitrile.

Crystal Form XIV is useful inter alia for purification of fluvastatin.It is also useful as a pharmaceutical composition.

The particle size distribution (PSD) of the forms can be studied byseveral techniques. The most common PSD techniques include sieving,sedimentation, electozone sensing (Coulter Counterj, microscopy and Lowangle Laser Light Scattering (LLALLS). Fluvastatin sodium Form XUVpreferably has a maximal particle size of less than about 400 μm, morepreferably less than about 300 μm, more preferably less than about 200μm, more preferably less than 100 μm, more preferably less than 50 μm.The maximal size can be seen under an optical microscope.

Pharmaceutical Compositions and Dosage Forms Containing—and Methods ofMedical Treatment Using The Novel Fluvastatin Sodium Forms

Fluvastatin exerts an antihypercholesterolemia and antihyperlipidemiaeffect in mammals, especially humans. Accordingly, fluvastatin sodiumForms XIV, are useful for delivering fluvastatin to the gastrointestinaltract, bloodstream and liver of humans and other mammals suffering fromor at risk of atherosclerosis. In particular, they are useful as activeingredients in pharmaceutical compositions and dosage forms. For thispurpose, they may be formulated into a variety of compositions anddosage forms for administration to humans and animals.

Pharmaceutical compositions of the present invention contain fluvastatinsodium Form XIV or mixtures thereof with other crystalline forms offluvastatin sodium, optionally in mixtures with one or more other activeingredient(s). In addition to the active ingredient(s), thepharmaceutical compositions of the present invention may contain one ormore excipients. Excipients are added to the composition for a varietyof purposes.

Diluents increase the bulk of a solid pharmaceutical composition and maymake a pharmaceutical dosage form containing the composition easier forthe patient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet may include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®, pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flow properties of non-compactedsolid composition and improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddie. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and die, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product fromthe die. Lubricants include magnesium stearate, calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,fluvastatin sodium Form XIV and any other solid excipients are dissolvedor suspended in a liquid carrier such as water, vegetable oil, alcohol,polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chonidrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention may also containa buffer such as guconic acid, lactic acid, citric acid or acetic acid,sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosage formsinclude dosage forms suitable for oral, buccal, rectal, parenteral(including subcutaneous, intramuscular, and intravenous), inhalant andophthalmic administration. Although the most suitable route in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and lozenges as well as liquid syrups,suspensions and elixirs.

An especially preferred dosage form of the present invention is acapsule containing the composition, preferably a powdered or granulatedsolid composition of the invention, within either a hard or soft shell.The shell may be made from gelatin and optionally contain a plasticizersuch as glycerin and sorbitol, and an opacifying agent or colorant. Anespecially preferred capsule filling contains, in addition to one ormore of the fluvastatin sodium crystalline forms of this invention, theexcipients magnesium stearate; microcrystalline cellulose,pregelatinized starch, sodium lauryl sulfate and talc.

Another especially preferred dosage form of this invention is acompressed tablet that contains, in addition to one or more of thefluvastatin sodium crystalline forms of this invention, the excipientsmicrocrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, potassium bicarbonate, povidone, magnesium stearate, ironoxide yellow, titanium dioxide and polyethylene glycol 8000.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filing may be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatemay then be tableted or other excipients may be added prior to tabletingsuch as a glidant and or lubricant.

A tableting composition may be prepared conventionally by dry blending.For instance, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may be compressed subsequently into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in the particularformulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Capsules, tablets and lozenges and other unit dosage forms preferablycontain a dosage equivalent to from about 10 to about 100 mgfluvastatin. Preferably the dosage is equivalent to from about 20 toabout 80 mg of fluvastatin. More particularly, imrnmediate oruncontrolled release dosage forms preferably contain the equivalent offrom abut 20 to about 40 mg of fluvastatin and extended release dosageforms preferably contain the equivalent of from about 60 to about 100 mgof fluvastatin, more preferably about 80 mg of fluvastatin.

Having thus described the present invention with reference to certainpreferred embodiments, the processes for producing Fluvastatin sodiumForms XIV of the present invention and techniques suitable foridentifying them are further illustrated by the examples which follow.These examples are provided for illustrative purposes only and are notintended to limit the invention in any way.

EXAMPLES

General

Powder X-ray diffraction data were obtained using methods known in theart on a SCINTAG powder X-ray diffractometer model XTRA equipped with asolid state detector. Copper radiation of 1.5418 Å was used. A roundaluminum sample holder with zero background was used. Detection limit:about 5% Form B.

DSC analysis was done on a Mettler 821 Star e. The weight of the sampleswas about 5 mg; the samples were scanned at a rate of 10° C./min from30° C. to 200° C. The oven was constantly purged with nitrogen gas at aflow rate of 40 ml/min. Standard 40 μl aluminum crucibles covered bylids with 3 holes were used.

TGA analysis was done using a Mettler M3 meter. The weight of thesamples was about 10 mg; the samples were scanned at a rate of 10°C./min from 25° C. to 200° C. The oven was constantly purged withnitrogen gas at a flow rate of 40 ml/min. Standard 70 μl aluminacrucibles covered by lids with 1 hole were used.

IR analysis was done using a Perkin Elmer “Spectrum One” FT-IRspectrometer in DRIFTt mode. The samples in the 4000-400 cm-1 intervalwere scanned 16 times with 4.0 cm-1 resolution.

The water content of fluvastatin sodium is measured by the methods knownin the art like Karl Fisher or thermogravimetric analysis.

Those skilled in the art will recognize the abbreviations used in thedisclosure, as they are in widespread use in the fields of medicinal andorganic chemistry. The abbreviations used include the following:

ACN acetonitrile DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide EtOHethanol Et₂O diethyl ether EtOAc ethyl acetate IPA isopropyl alcoholMeOH methanol MTBE methyl tert-butyl ether MEK methyl ethyl ketone THFtetrahydrofuranPreparative

All the preparations described below were carried out on fluvastatinsodium Form B except where indicated otherwise.

Preparation of Fluvastatin Sodium Crystal Form XIV

Example 1

Fluvastatin sodium (3.0 g) was suspended in a mixture of toluene (60 ml)and hexanes (60 ml) at reflux temperature for 19 h. Then, the mixturewas cooled to room temperature. The product was isolated by filtrationunder nitrogen, washed with hexanes (2×10 ml) and dried at 50° C. in avacuum oven for 22 h to obtain 1.2 g (39%) of fluvastatin sodium crystalForm XIV.

Example 2

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and ethanol (7.5 ml). The mixture was heated toreflux and stirred until the starting material was no longer detectableby HPLC. Then, 58 ml of MTBE was dripped into the solution over 1.5 h.Turbidity appeared in the solution. The mixture was cooled slowly toroom temperature and stirred overnight. The product was isolated byfiltration under nitrogen, washed with MTBE (50 ml) and dried at 50° C.in a vacuum oven for 24 h to obtain 2.21 g (72.3%) of fluvastatin sodiumForm XIV.

Example 3

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in ethanol (15 ml). The mixture was stirred at about 70° C. for 1.75 h,after which the starting material was no longer detectable by HPLC.Then, 40 ml of MTBE was dripped into the solution. The mixture wascooled slowly to room temperature and stirred overnight. The productcould not be filtrated so another 100 ml of MTBE was added and themixture was stirred over the weekend. The product was isolated byfiltration under nitrogen and dried at 50° C. in a vacuum oven for 24 hto obtain 1.45 g (71.2%) of fluvastatin sodium Form XIV.

Example 4

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in propan-2-ol (15 ml). The mixture was stirred at about 70° C. for 2 h,after which time the starting material was no longer detectable by HPLC.Then, acetonitrile (40 ml) was dripped into the mixture. The mixture wascooled slowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetonitrile (50 ml)and dried at 50□C in a vacuum oven for 24 h to obtain 1.54 g (75.5%) offluvastatin sodium Form XIV.

Example 5

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated toreflux and 1 ml of propan-2-ol was added. After 2 h, the mixture wascooled to room temperature and stirred for 2 h. MTBE (60 ml) was drippedinto the solution over 20 min and the resulting mixture was stirred foranother 1.5 h. The product was isolated by filtration under nitrogen,washed with MTBE and dried at 50° C. in a vacuum oven for 24 h to obtain1.9 g (62%) of fluvastatin sodium Form XIV.

Example 6

Fluvastatin sodium (3.0 g) was dissolved in a mixture of propan-2-ol (50ml) and water (5 ml) at reflux temperature. MTBE (50 ml) was addeddropwise and the mixture was stirred at reflux temperature for ½ h.Then, the mixture was cooled to room temperature and stirred at thistemperature for 16 h. Another portion of MTBE (50 ml) was added toobtain further precipitation. After 5 h, the product was isolated byfiltration under nitrogen, washed with MTBE (2×10 ml) and dried at 50°C. in a vacuum oven for 24 h to obtain fluvastatin sodium Form XIV (1.4g, 48%).

Example 7

Fluvastatin sodium (30.0 g) was dissolved in a mixture of propan-2-ol(500 ml) and water (50 ml) at reflux temperature. The obtained solutionwas stirred at reflux temperature for 1.5 h. Then, the mixture wascooled to room temperature and stirred at this temperature for 16 h. Theproduct was isolated by filtration under nitrogen, washed withpropan-2-ol (2×100 ml) and dried at 50° C. in a vacuum oven for 23 h toobtain fluvastatin sodium Form XIV (14.8 g, 49%).

Example 8

Fluvastatin sodium (3.0 g) was dissolved in a mixture of propan-1-ol (30ml) and water (3 ml) at reflux temperature. MTBE (60 ml) was addeddropwise and the mixture was stirred at reflux temperature for 1 h.Then, the mixture was cooled to room temperature and stirred at thistemperature for 3 h. The product was isolated by filtration undernitrogen, washed with MTBE(2×15 ml) and dried at 50° C. in a vacuum ovenfor 20 h to obtain fluvastatin sodium Form XIV (2.2 g, 74%).

Example 9

Fluvastatin sodium (4.0 g) was dissolved in a mixture of THF (20 ml) andwater (1 ml) at reflux temperature. MTBE (40 ml) was added dropwise andthe mixture was stirred at reflux temperature for 1 h. Then, the mixturewas cooled to room temperature and stirred at this temperature for 4.5h. The product was isolated by filtration under nitrogen, washed withMTBE (2×20 ml) and dried at 50° C. in a vacuum oven for 24 h to obtainfluvastatin sodium Form XIV (1.9 g, 47%).

Example 10

Fluvastatin sodium (4.0 g) was dissolved in a mixture of THF (20 ml) andwater (1 ml) at reflux temperature. Dichloromethane (40 ml) was addeddropwise and the mixture was stirred at reflux temperature for 40minutes. Then, the mixture was cooled to room temperature and stirred atthis temperature for 24 h. The product was isolated by filtration undernitrogen, washed with dichloromethane (2×20 ml) and dried at 50° C. in avacuum oven for 24 h to obtain fluvastatin sodium Form XIV (3.8 g, 94%).

Example 11

Fluvastatin sodium (4.0 g) was dissolved in a mixture of THF (20 ml) andwater (1 ml) at reflux temperature. Hexanes (40 ml) was added dropwiseand the mixture was stirred at reflux temperature for 40 minutes. Then,the mixture was cooled to room temperature and stirred at thistemperature for 4 h. The product was isolated by filtration undernitrogen, washed with Dichloromethane (2×20 ml) and dried at 50° C. in avacuum oven for 24 h to obtain fluvastatin sodium Form XIV (2.6 g, 66%).

Example 12

A 250 ml round bottom flask was loaded with fluvastatin (20.0 g, 47mmole), water (60 ml) and ethanol (100 ml) and NaOH (1.94 g). Themixture became clear and was stirred until the raw material wasn'tobserved by HPLC. The solution was filtered and the EtOH wasdistillated. Water (157 ml) was added to the slurry mixture, which wasextracted with EtOAc (2×100 ml). The clear solution was divided to 6parts.

Example 13

A solution of fluvastatin sodium that was prepared as described inExample 12 (42 ml) was concentrated until the water volume was ca. 1.5ml then IPA (68 ml) was added and the mixture was stirred at roomtemperature for 18 h. The product was isolated by filtration undernitrogen, washed with IPA (20 ml) and dried at 40□C in a vacuum oven for24 h to obtain 1.12 g (ca. 33%) of fluvastatin sodium crystal Form XIV.

Example 14

A solution of fluvastatin sodium that was prepared as described inExample 12 (42 ml) was concentrated until the water volume was ca. 1.8ml then acetonitrile (68 ml) was added and the mixture was stirred atroom temperature for 17.5 h. The product was isolated by filtrationunder nitrogen, washed with acetonitrile (20 ml) and dried at 40□C in avacuum oven for 24 h to obtain 2.18 g (ca. 64%) of fluvastatin sodiumcrystal Form XIV (Form B: non-detectable).

Example 15

A solution of fluvastatin sodium that was prepared as described inExample 12 (42 ml) was concentrated until the water volume was ca. 0.8ml then acetone (68 ml) was added and the mixture was stirred at roomtemperature for 24.5 h. The product was isolated by filtration undernitrogen, washed with acetone (20ml) and dried at 40° C. in a vacuumoven for 22 h to obtain 2.65 g (ca. 78%) of fluvastatin sodium crystalForm XIV.

Example 16

Acetonitrile (30 ml) and brine (15 ml) added to solution of Fluvastatinsodium that was prepared as described in example 12 (30 ml) The phaseswere separated and the organic phase was extracted with brine (15 ml),then acetonitrile (30 ml) was added to the organic phase which wasstirred at room temperature over night. The product was isolated byfiltration under nitrogen, washed with acetonitrile (30 ml) and dried at40° C. in a vacuum oven for 24 h to obtain 1.99 g (ca. 80%) offluvastatin sodium crystal Form XIV (+NaCl residue).

Example 17

EtOAc (32 ml) and brine (16 ml) added to solution of fluvastatin sodiumthat was prepared as described in Example 12 (32 ml contains ca. 3 gfluvastatin sodium) The phases were separated and the organic phase wasextracted with brine (10 ml), then EtOAc (32 ml) was added to theorganic phase which was stirred at room temperature over night. Theproduct was isolated by filtration under nitrogen, washed with EtOAc (90ml) and dried at 40° C. in a vacuum oven for 24 h to obtain 2.43 g (ca.80%) of fluvastatin sodium crystal Form XIV (+NaCl residue).

Example 18

A 250 ml round bottom flask was loaded with fluvastatin tert-butyl ester(3.0 g, 6.4 mmole), water (27 ml), THF (7.5 ml) and NaOH (0.29 g). Themixture was stirred for 1.5 h then THF (2.5 ml) was added. After another0.5 h THF (2.5 ml) was added again and the solution became clear. Thesolution was stirred for another 5 h then extracted with EtOAc (2×20ml). The clear solution was divided to 2 parts.

Example 19

A solution of fluvastatin sodium that was prepared as described inExample 18 was concentrated until the weight was 1.51 g thenacetonitrile (30 ml) was added and the mixture was stirred at roomtemperature over night. The product was isolated by filtration undernitrogen flow, washed with acetonitrile and dried at 40° C. in a vacuumoven for 24 h to obtain 0.56 g (ca. 40%) of fluvastatin sodium crystalForm XIV.

Example 20

A solution of fluvastatin sodium that was prepared as described inExample 18 was concentrated until the weight was 1.5 g, then acetone (30ml) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen flow,washed with acetone and dried at 40° C. in a vacuum oven for 24 h toobtain 1 g (ca. 72%) of fluvastatin sodium crystal Form XIV.

Example 21

Water (56 ml), acetonitrile (200 ml) and FDE-tBu (40 gr) were added to a1 L stirred reactor. At 25° C., 7.5 gr of 47% NaOH solution was added,and the mixture was heated to 35° C. The mixture became clear during thehydrolysis. End of reaction was determined by HPLC (−3-4 hr). Themixture was then cooled to 25° C. Acetonitrile (600 ml) was added to themixture. The mixture was stirred for ˜5 hr to increase yield, and theformed precipitate was filtered under vacuum. The wet product was washedwith 120 ml of acetonitrile. The wet product was dried in a vacuum ovenat 40° C. to obtain FLV Na form XIV crystals (Yield: 87%).

Preparation of Fluvastatin Sodium Crystal Form XIV, Having a Peak at12.4±0.2 Degrees two-theta in the XRD Pattern

Example 22

A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester(4.0 g, 8.56 mmole), MeOH (24 ml) and NaOH (0.35 g) in water (2 ml). Themixture was heated to 35° C. After 2 h water (10 ml) was added and themixture was stirred for another 4.5 h then the MeOH was evaporated. Thevolume of the water was completed to 8 vol. and the mixture wasextracted with EtOAc (24 ml). The aqua solution was evaporated tocontain ca. 1 vol. water and ACN (60 ml) was added. The solution wasstirred at room temperature over night. The product was isolated byfiltration under nitrogen, washed with ACN (15 ml) and dried at 40° C.in a vacuum oven for 24 h to obtain 3.18 g (85.7%) of fluvastatin sodiumcrystal form XIV, having a peak at 12.4±0.2 degrees two-theta in the XRDpattern

Example 23

A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester(4.0 g, 8.56 mmole), MeOH (24 ml) and NaOH (0.31 g) in water (2 ml). Themixture was heated to 35° C. and stirred for 4.5 h then water (10 ml)was added and the MeOH was evaporated. The volume of the water wascompleted to 8 vol. and the mixture was extracted with EtOAc (25 ml).The aqueous solution was evaporated to contain ca. 1 vol. water and ACN(60 ml) was added. The solution was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washedwith ACN and dried at 40° C. in a vacuum oven for 24 h to obtain 1.06 g(28.6%) of fluvastatin sodium crystal form XIV, having a peak at12.4±0.2 degrees two-theta in the XRD pattern.

Preparation of Fluvastatin Sodium Crystal Form XIV Through Form LXXXVII

Example 24

Into a 1 L reactor equipped with mechanical stirrer and thermometer, 40g of fluvastatin diol tert-butyl ester and 240 ml MeOH were charged.3.54 g of NaOH dissolved in 20 ml water were added and the mixture washeated to 35° C. After 1 hour the solution became clear and 100 ml Waterwere added. The reaction solution was maintained at 35° C. under mixingduring 4 hours. The MeOH was distilled by vacuum at 40° C. and water(230 ml) was added in order to complete the volume to 8 volumes vs. 1 grof fluvastatin diol tert-butyl ester. he aqueous mixture was extractedwith 240 ml MTBE. After vacuum filtration the water was distilled byvacuum at 60° C. ACN (120 ml) was added at room temperature is withvigorously stirring in order to get maximum dissolving. The amount ofwater in the clear solution was determined by Karl Fisher method andcalculated to be 1.6 vol then 680 ml of ACN were added. The reactionsolution was maintained at 25° C. under mixing over night. The productwas isolated by vacuum filtration under N₂ flow, washed with ACN (100ml) (crystal Form LXXXVII), dried in vacuum oven at 40° C. for 25 hoursto obtain 29.2 g (78.8%) fluvastatin sodium crystal Form XIV.

Example 25

Fluvastatin diol tert-butyl ester (80 g), methanol (480 ml), 47% NaOHsolution (14.87 g) and water (32.1 ml) were added into a stirred reactorand heated to 35° C. When the solution became clear (˜1 hr), additionalwater (80 ml) was added. The solution was stirred at 35° C. foradditional 2 hours. Methanol was distillated by vacuum distillation at60 mmHg and a jacket temp of 40° C. When distillation ended, ACN (240ml) and water (54 ml) were added until dissolution occurred. ACN (680ml) was added to half of the solution (193 g) at 25° C. The productprecipitated during the ACN addition. The mixture was stirred at 25° C.for additional 12 hours, then filtered with vacuum and the wet productwas washed with ACN (120 ml). XRD detection for the wet product is FormLXXXVII (Form B: non-detectable). The wet product was dried in a vacuumoven at 40° C. for 12-15 hours. XRD detection for the dry product wasForm XIV.

Example 26

Fluvastatin diol tert-butyl ester (40 gr), methanol (240 ml), 47% NaOHsolution (7.44 gr) and water (16.1 ml) were added into a stirred reactorand heated to 35° C. When the solution became clear (˜1 hr) additionalwater (40 ml) was added. The solution was stirred at 35° C. foradditional 2 hours. Methanol was distillated by vacuum distillation at60 mmHg and a jacket temp of 40° C. When distillation ended, ACN (120ml) and water (30 ml) were added until dissolution occurred. ACN (680ml) was again added to the solution at 25° C. The product precipitatedduring the ACN addition. The mixture was stirred at 25° C. foradditional 12 hours, then filtered with vacuum and the wet product waswashed with ACN (120 ml). XRD detection for the wet product was FormLXXXVII. The wet product was dried in a vacuum oven at 40° C. for 12-15hours. XRD detection for the dry product was Form XIV.

Example 27

500 g of Fluvastatin diol tert-butyl ester and 3000 ml of methanol wereadded to a 10 liter reactor and stirred at room temperature. A solutionof 45.5 g of 100% NaOH and 250 ml water was added. The mixture washeated to 35-36 deg. by setting the jacket temperature to 40° C. Whenthe mixture became a clear solution (˜60 min). According to KF result,the solution contained 2.7 vol. of water (per g Fluvastatin dioltert-butyl ester).” 1250 ml of water were added. End of reaction wasdetermined by HPLC after 90 min. Methanol was distilled at 40° C. injacket and <60 mmHg vacuum. 2680 ml water were added and the mixture wascooled to 5° C. and stirred overnight. In the morning, 3000 ml of MTBEwere added. The mixture was heated to 25° C. and stirred for 20 min.Stirring was stopped for phase separation. The aqueous phase wasdistilled for water removal at 60° C. and <60 mmHg vacuum. 1500 ml ofACN were added at 25° C. and the mixture became a clear solution. 1500ml of ACN were added to the solution and the mixture was stirred at 25°C. overnight (˜16 h). Precipitation occurred during ACN addition. Theproduct was filtered with suction and washed with 1500 ml of ACN. 610 gof wet product were obtained (detected to be form 87 by XRD). Wetproduct was dried in a vacuum oven at 40° C. for 24 h. 380 g of dryproduct was obtained (detected to be form XIV by XRD).

Stability Tests

Example 28

Fluvastatin Na Form XIV was stable after exposure to relative humiditiesbetween 0-100% RH for 7 days and equilibrated at water contents between3-16%. The results are summarized in the next table. Fluvastatin FormXIV is in monohydrate, sesquihydrate, dihydrate, hemipentahydrate,tryhydrate, tetrahydrate and pentahydrate forms.

Water uptake (%) and Crystal form of Fluvastatin Na Crystal form XIVEquilibrated at different Relative humidities for 7 days

Water content Weight loss RH by KF (%) by TGA (%) Form 100 15.5 XIV 8013.2 XIV 60 10.2 XIV 40 7.0 XIV 20 4.8 XIV 0 3.2 XIV T = 0 5.9 6.0 XIV

Having thus described the invention with reference to particularpreferred embodiments and illustrated it with examples, those in the artmay appreciate modifications to the invention as described andillustrated that do not depart from the spirit and scope of theinvention as defined by the claims which follow.

1. A process for preparing a crystalline form of fluvastatin sodiumcharacterized by a PXRD pattern with peaks at 3.8, 11.1, 12.9, 17.8 and21.7±0.2 degrees two-theta comprising: a) combining a C₁ to C₄ alkylester of fluvastatin with acetonitrile at a ratio of about 1:4-6 (Kg/L)of the ester to acetonitrile, and with water at a ratio of about1:1.3-1:2 (Kg/L) of the ester to the water, to obtain a mixture; b)combining sodium hydroxide with the mixture to hydrolyze the ester,thereby obtaining a solution, wherein if aqueous sodium hydroxide isused, the water ratio does not exceed that provided in step (a); c)combining additional acetonitrile with the solution to precipitatecrystalline fluvastatin sodium; and d) recovering crystallinefluvastatin sodium.
 2. The process of claim 1, wherein the alkyl esteris combined with acetonitrile at a ratio of about 1:5-6(Kg/L).
 3. Theprocess of claim 1, wherein addition of the acetonitrile in step (c)results in a ratio of about 1:15 to about 1:25 (Kg/L).
 4. The process ofclaim 3, wherein the ratio is about 1:19.5-1:20.5 (Kg/L).
 5. The processof claim 1, wherein the ratio of the ester to water is about 1:1.3-1:1.8(Kg/L).
 6. The process of claim 1, wherein the solution is maintainedafter addition of acetonitrile for about 2 to about 24 hours.
 7. Theprocess of claim 6, wherein the solution is maintained for about 5hours.
 8. The process of claim 1, wherein prior to combining withacetonitrile, the mixture is heated to a temperature of about 30° C. toabout 40° C. to facilitate dissolution.
 9. The process of claim 8,wherein the mixture is heated to a temperature of about 35° C.
 10. Theprocess of claim 8, wherein after heating, the solution is cooled toroom temperature.
 11. The process of claim 1, wherein the ester ist-butyl.
 12. The process of claim 1, wherein if an ester other than thebutyl ester is used, the ratio is based on molar weight of butyl ester,and is adjusted, by calculating molar weight of the other ester inrelation to the butyl ester of fluvastatin.
 13. A process for preparinga crystalline form of fluvastatin sodium characterized by a PXRD patternwith peaks at 3.8, 11.1, 12.9, 17.8 and 21.7±0.2 degrees two-thetacomprising: a) preparing a solution of fluvastatin sodium inacetonitrile at a ratio of about 1:4-6 (Kg/L) of fluvastatin toacetonitrile, and in water at a ratio of about 1:1.3-1:2 (Kg/L) offluvastatin to water, wherein the ratio is based on the molar weight ofbutyl ester of fluvastatin, and is adjusted if an ester other than thebutyl ester is used, by calculating molar weight of the other ester inrelation to the butyl ester of fluvastatin; b) combining the solutionwith an additional amount of acetonitrile to precipitate the crystallinefluvastatin sodium; and c) recovering the crystalline fluvastatinsodium.
 14. The process of claim 13, wherein the fluvastatin toacetonitrile ratio is about 1:5-6 (Kg/L).
 15. The process of claim 13,wherein addition of acetonitrile in step (b) results in a ratio of about1:15-1:25 (Kg/L).
 16. The process of claim 15, wherein the ratio isabout 1:19.5 to 1:20.5 (Kg/L).
 17. The process of claim 13, wherein theratio of fluvastatin to water is about 1:1.3-1:1.8 (Kg/L).